1. Field
Agents are needed for treating diseases and disorders related to aberrant cystic fibrosis transmembrane conductance regulator protein (CFTR) such as increased intestinal fluid secretion, secretory diarrhea, and polycystic kidney disease. Small molecule conjugates are described herein that are potent inhibitors of CFTR activity and that may be used for treating such diseases and disorders.
2. Description of the Related Art
Diarrheal disease in children is a global health concern: approximately four billion cases among children occur annually, resulting in two million deaths. Travelers' diarrhea affects approximately 6 million people per year. Antibiotics are routinely used to treat diarrhea; however, the antibiotics are ineffective for treating many pathogens, and the use of these drugs contributes to development of antibiotic resistance in other pathogens.
The cystic fibrosis transmembrane conductance regulator protein (CFTR) is a cAMP-activated chloride (Cl−) channel expressed in epithelial cells in mammalian airways, intestine, pancreas, and testis. Certain mutations in CFTR lead to the hereditary disease cystic fibrosis (see, e.g., Quinton, Physiol. Rev. 79:S3-S22 (1999); Boucher, Eur. Respir. J. 23:146-58 (2004)). CFTR is expressed in enterocytes in the intestine and in cyst epithelium in polycystic kidney disease (see, e.g., O'Sullivan et al., Am. J. Kidney Dis. 32:976-983 (1998); Sullivan et al., Physiol. Rev. 78:1165-91 (1998); Strong et al., J. Clin. Invest. 93:347-54 (1994); Mall et al., Gastroenterology 126:32-41 (2004); Hanaoka et al., Am. J. Physiol. 270:C389-C399 (1996); Kunzelmann et al., Physiol. Rev. 82:245-289 (2002); Davidow et al., Kidney Int. 50:208-18 (1996); Li et al., Kidney Int. 66:1926-38 (2004); Al-Awqati, J. Clin. Invest. 110:1599-1601 (2002); Thiagarajah et al., Curr. Opin. Pharmacol. 3:594-99 (2003)). Hormones, toxins, such as cholera toxin, and increased cellular Ca2+ lead to an increase in cAMP activation of cAMP-dependent protein kinase, which phosphorylates the CFTR Cl− channel.
CFTR provides a pathway for the movement of Cl− ions across the apical membrane and thus regulates the rate of transepithelial salt and water transport. CFTR mediates transepithelial fluid secretion in secretory diarrhea; therefore, inhibitors of CFTR function may be useful therapeutics for treating this disease. The morbidity and mortality associated with secretory diarrhea indicate an imperative need for potent inhibitors of CFTR activity.